Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers

Abstract

The present invention relates to dabigatran etexilate and related substances and use of the substances as reference standards and markers. There are also provided processes of detecting the substances in samples of dabigatran etexilate, or pharmaceutically acceptable salts or solvates thereof, and also for analyzing the purity of samples of dabigatran etexilate, or pharmaceutically acceptable salts or solvates thereof. There are still further provided processes of preparing dabigatran etexilate and related substances, and pharmaceutical compositions containing the same.

The invention claimed is: 
     
       1. A compound of formula (B) 
       
         
           
           
               
               
           
         
         wherein R 2  is hydroxyl, C 1-4  alkoxy, or NH 2 . 
       
     
     
       2. A compound (B1) according to  claim 1 , wherein R 2  is a hydroxyl group. 
     
     
       3. A compound (B) according to  claim 1 , wherein R 2  is C 1-4  alkoxy. 
     
     
       4. A compound (B2) according to  claim 3 , wherein the C 1-4  alkoxy is a methoxy group. 
     
     
       5. A compound (B3) according to  claim 3 , wherein the C 1-4  alkoxy is an ethoxy group. 
     
     
       6. A compound (B4) according to  claim 1 , wherein R 2  is a NH 2  group. 
     
     
       7. A compound according to  claim 1  in isolated form. 
     
     
       8. A method for analyzing the purity of dabigatran etexilate or a salt or solvate thereof in a sample comprising determining the amount present in the sample of one or more of compounds of formula (B). 
     
     
       9. A method according to  claim 8 , wherein the dabigatran etexilate or a salt or solvate in the sample is derived from one or more sources selected from the group consisting of dabigatran etexilate active pharmaceutical ingredient, a pharmaceutical composition comprising dabigatran etexilate, dabigatran etexilate salt or solvate thereof, and a pharmaceutical composition comprising dabigatran etexilate salt or solvate thereof. 
     
     
       10. The method of  claim 8 , wherein the purity of dabigatran etexilate or a salt or solvate thereof is analyzed by determining the amount of compound (B3) present in the sample. 
     
     
       11. A method for determining the presence of one or more compounds of formulae (B) in a sample comprising dabigatran etexilate or a salt or solvate thereof, said method comprising:
 (a) providing a sample solution comprising dabigatran etexilate or a salt or solvate thereof; 
 (b) providing a reference marker solution comprising one or more compounds of formulae (B); and 
 (c) subjecting the sample solution and the reference marker solution to chromatographic conditions to obtain a retention factor of the components of the sample solution and of the components of the reference marker solution; and 
 (d) comparing the retention factor of the components of the sample solution with the retention factor of the components of the reference marker solution. 
 
     
     
       12. The method of  claim 11 , wherein the dabigatran etexilate salt is dabigatran etexilate mesylate. 
     
     
       13. The method of  claim 12 , wherein the chromatographic conditions are the same for the sample solution and the reference marker solution. 
     
     
       14. The method of  claim 11  further comprising quantifying the amount of one or more compounds of formulae (B) present in the sample solution. 
     
     
       15. A method for preparing dabigatran etexilate, or a salt or solvate thereof, suitable for pharmaceutical use comprising:
 (a) providing dabigatran etexilate, or a salt or solvate thereof; 
 (b) assessing the purity of said dabigatran etexilate, or a salt or solvate thereof, using the method of  claim 14 ; and 
 optionally subjecting the dabigatran etexilate, or a salt or solvate thereof, to one or more purification steps. 
 
     
     
       16. The method according to  claim 15  comprising:
 (a) providing dabigatran etexilate, or a salt or solvate thereof; 
 (b) assessing the purity of said dabigatran etexilate, or a salt or solvate thereof; 
 (c) subjecting the dabigatran etexilate, or a salt or solvate thereof, to a purification step; and 
 (d) optionally, repeating steps (b) and (c) one or more times. 
 
     
     
       17. The method according to  claim 16 , wherein said compound of formulae (B) in step (b) is a compound of formula (B1). 
     
     
       18. The method according to  claim 16 , wherein said compound of formulae (B) in step (b) is a compound of formula (B3).